Tetrapeptide amides in the treatment of hypertension

ABSTRACT

The invention relates to tetrapeptides of the formula I:   &lt;IMAGE&gt; which are useful as renin inhibition/antihypertensive agents.

BACKGROUND OF THE INVENTION

The present invention relates to tetrapeptide amides of Formula I which,surprisingly, have been found to possess renin inhibition properties andare thus useful in the treatment of hypertension.

Hypertension is a condition caused by any of a variety of functionalabnormalities. For example, hypertension may be related to abnormalitiesin adrenergic, cholinergic, or neuromuscular interactions; in hormonalbalance; or in kidney function, which malfunctions often are caused byabnormalities of the other systems. Treatment with drugs that areintended to act at some receptor site involved in one of themalfunctioning systems has frequently been the basis of therapy. Forexample, numerous neural receptor blockers are known to act asantihypertensive agents, and diuretics are commonly used to counteractthe effects of fluid retention associated with kidney dysfunction. Eachof these regimens, however, is associated with side effects oftenrelated to inadequate specificity. See generally L. S. Goodman and A.Gilman, eds. The Pharmacological Basis of Therapeutics (New York, 1975),Fifth Edition, Chaps. 26, 27, 28, 30, 33, 39, 40.

The renin-angiotensin system has been implicated in hypertension. SeeGoodman and Gilman, supra, pp. 630-637. The enzyme renin converts theplasma protein angiotensinogen to the essentially inactive decapeptideangiotensin I, which in turn is proteolytically converted by theso-called "converting enzyme" to the potently vasoactive octapeptideangiotensin II. Various peptidases further hydrolyze angiotensin II toessentially inactive peptide fragments. In addition to regulating bloodpressure, angiotensin also stimulates the secretion of aldosterone andthus is intimately involved in regulating the sodium-potassium balance.Thus, inhibition of renin could be an important means of controllinghigh blood pressure. Certain short-chain peptide analogs ofangiotensinogen segments have been reported to inhibit renin activity.K. Poulsen, J. Burton, and E. Haber, Biochemistry, 12, 3877-3882 (1973);J. Burton, K. Poulsen, and E. Haber, Biochemistry, 14, 3892-3898 (1975);J. Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad.Sci. U.S.A., 77, 5476-5479 (1980). Peptide inhibitors of renin activityhave also been reported to lower blood pressure in primates. See J.Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad.Sci. U.S.A., 77, 5476-5479 (1980); R. J. Cody, J. Burton, G. Evin, K.Poulsen, J. A. Herd, and E. Haber, Biochem. Biophys. Res. Commun., 97,230-235 (1980). The present invention provides peptide amides of shorterlength which are renin inhibitors and exhibit antihypertensive activity.

INFORMATION DISCLOSURE

U.S. Pat. No. 4,316,892 relates to certain derivatives of methionineenkephalin derivatives useful as analgesic agents. Also see Morgan U.S.Pat. No. 4,178,371 relating to analogous enkephalin type analgesics.Commonly assigned, allowed co-pending U.S. application Ser. No. 539,458,filed Oct. 6, 1983, claims enkephalin derivatives in which the aminoacid in the fourth position is a hexahydrophenylalanine residue as beinguseful as analgesic agents. The foregoing application includes thestatement that some of the compounds may have anti-hypertensive activityalthough no biological results are set forth. In contrast, the compoundsof the present invention comprise those in which the amino acid residuein the fourth position is phenylalanine, or alkyl substitutedphenylalanine derivatives.

SUMMARY OF THE INVENTION

The present invention particularly provides tetrapeptide amidesaccording to Formula I. ##STR2## wherein R₁ is: (a) hydrogen; or

(b) alkyl of 1 to 6 carbon atoms, inclusive;

wherein R₂ is:

(a) alkyl of 1 to 6 carbon atoms, inclusive; or

(b) ##STR3## m being either zero, 1 or 2; wherein R₃ is:

(a) hydrogen; or

(b) alkyl of 1 or 2 carbon atoms; inclusive;

wherein R₄ is:

(a) phenyl, optionally substituted by alkyl of 1 to 6 carbon atoms,inclusive:

wherein R₅ is:

(a) hydrogen; or

(b) alkyl of 1 to 6 carbon atoms, inclusive;

wherein R₆ is:

(a) carboxy;

(b) alkoxycarbonyl of 2 to 7 carbon atoms, inclusive;

(c) CONH₂ ;

(d) N,N-dialkylcarbamoyl of 3 to 7 carbon atoms, inclusive;

(e) hydroxy; or

(f) alkanoyloxy of 2 to 7 carbon atoms, inclusive;

wherein R₇, R₈, and R₉ are H or alkyl of 1 to 6 carbon atoms, and may bethe same or different;

wherein R₁₀ is:

(a) hydrogen;

(b) hydroxy; or

(c) alkoxycarbonyloxy wherein the alkoxy portion is from 1 to 6 carbonatoms, inclusive;

wherein n is an integer of from 3 to 10 inclusive and thepharmocologically acceptable acid addition salts thereof.

Examples of alkoxy of one to six carbon atoms, inclusive, are methoxy,ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the isomeric formsthereof.

Examples of alkyl of one to six carbon atoms inclusive, are methyl,ethyl, propyl, butyl, pentyl, and hexyl and the isomeric forms thereof.

The renin inhibition activity of the compounds of this inventionillustrated in the examples was tested by the following method.Pepstatin and the octapeptideprolylhistidylprolylphenylalanylhistidylleucylphenylalanylvalyltyrosine(or, "Pro-[Phe⁶ ]octapeptide"; see J. Burton, K. Poulsen, and E. Haber,Biochemistry, 14, 3892-3898 (1975)) are active in this assay.

Inhibition of Human Renin

International reference standard human renin, isolated from kidneys, wasobtained from the World Health Organization International Laboratory forBiological Standards (National Institute for Biological Standards andControl, London, England). Renin activity is defined in "Goldblattunits" (GU), the quantity that, when injected directly into the bloodstream of an unanesthetized dog, raises the direct mean femoral arteryblood pressure by 30 mm Hg in about two minutes. E. Haas, L. Lewis, P.Scipione, and T. J. Koshy, Hypertension, 1, 112-117 (1979). Humanangiotensinogen was used as an unisolated component of human bloodplasma. The enzyme inhibition assay, see K. Poulsen, J. Burton, and E.Haber, Biochemistry, 12, 3877-3882 (1973), involved a two-hourincubation at 37° C. of the following final concentrations of reagents(0.25 ml total volume): 0.1 mGU/ml human renin; 0.05 ml human plasma; 6mM disodium EDTA; 2.4 mM phenylmethylsulfonyl fluoride and 1.5 mM8-hydroxyquinoline (angiotensinase inhibitors); 0.4 mg/ml bovine serumalbumin; and 0.024 neomycin sulfate in 100 mM Tris-acetate buffer (pH7.5). The enzymatic reaction was terminated by boiling the mixture forten minutes. The quantity of angiotensin I formed was determined byradioimmunoassay, using the general method used in the angiotensin Iradioimmunoassay kit of New England Nuclear. Test compounds wereconsidered active if inhibition was greater than 20%.

The following tests further illustrate the in vivo methods fordetermining antihypertensive activity of the compounds of thisinvention.

Spontaneously Hypertensive Rat Assay--Indirect Measurement

Male spontaneously hypertensive rats were used in this assay. Initialsystolic blood pressure was measured using a caudal plethysmographimmediately before administration of test compounds. For initialscreening the test compounds were administered intragastrically at adose of 50 mg per kg of body weight. Blood pressure readings wereobtained at four hours (and in some cases also at 24 hours) afterdosing. A compound was rated active if the post-treatment blood pressurewas significantly depressed (P≦0.05) relative to the initial pressurereading.

Spontaneously Hypertensive Rat Assay--Direct Measurement

Male spontaneously hypertensive rats were used in this assay. Using apreviously implanted arterial catheter, initial mean arterial bloodpressure was measured directly immediately before administration of testcompounds. For initial screening the test compounds were administeredintragastrically at a dose of 50 mg per kg of body weight. Bloodpressure readings were usually obtained at 1, 2, 3, and 4 hours afterdosing. A compound was rated active if the mean post-treatment bloodpressure was significantly different (P≦0.05) from that of theconcurrent placebo control group.

Renal-ligated Hypertensive Rat Assay

Male Sprague Dawley rats aged 11 to 15 weeks old were used in this test.Three hours after bilateral ligation of the renal arteries, the meanarterial blood pressure (measured directly with previously implantedarterial catheters) and the plasma renin activity increasedsignificantly (P≦0.05) higher than in sham-operated animals. Testcompounds were administered intra-arterially at a dose of 10 mg per kgof body weight, and blood pressure changes were monitored directly at 5,10, and 15 minutes after injection. A compound was considered active ifthe post-treatment blood pressure was significantly (P≦0.05) depressedrelative to the placebo control. Under these test conditions pepstatinsignificantly reduced both mean arterial blood pressure and plasma reninactivity.

Rhesus Monkey Blood Pressure Test

Rhesus monkeys were sodium depleted by means of a fruit diet incombination with intramuscular furosemide injections (0.5 mg per kg ofbody weight) given twice daily for four days. This procedure causesblood pressure to become dependent on plasma renin activity. J. Burton,R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad. Sci. U. S.A., 77, 5476-5479 (1980). On the fifth day the animals were anesthetizedwith ketamine (100 mg administered intravenously). The femoral arterywas cannulated for blood pressure measurement and a percutaneous venouscannula was inserted for test compound administration. The animals wereallowed to recover from anesthesia and were restrained in a transparentplastic chair. Blood pressure was monitored continuously both before andafter test compounds were administered (at 3 mg per kg of body weight).A compound was considered active if post-treatment mean blood pressurewas significantly (P≦0.05) depressed relative to preadministration meanblood pressure. Under these test conditions captopril at 0.1 mg per kgand "renin inhibitory peptide" (RIP, orprolylhistidylprolylphenylalanylhistidylphenylalanylphenylalanylvalyltyrosyllysine;see Burton et al., supra) at 1.0 mg per kg significantly lowered meanblood pressure. By virtue of their renin inhibition activity, thecompounds of Formula I are useful in treating or preventing symptoms ofhypertension in humans and animals. A physician of ordinary skill couldreadily determine a subject who is exhibiting such symptoms. Regardlessof the route of administration selected, the compounds of the presentinvention are formulated into pharmaceutically acceptable dosage formsby conventional methods known to the pharmaceutical art. The compoundscan be administered in such oral dosage forms as tablets, capsules,pills, powders, granules, suspensions, or solutions. They may alsointroduced in the form of eyedrops, intraperitoneally, subcutaneously orintramuscularly, using forms known to the pharmaceutical art. In generalthe preferred form of administration is oral.

An effective but nontoxic quantity of the compound is employed intreatment. The dosage regimen for preventing or treating symptoms by thecompounds of this invention is selected in accordance with a variety offactors including the type, age, weight, sex, and medical condition ofthe mammal, the severity of the symptoms, the route of administration ofthe particular compound employed. An ordinary skilled physician willreadily determine and prescribe the effective amount based on the routeof administration of the antihypertensive agent to prevent or arrest theprogress of the condition. In so proceeding, the physician could employrelatively low dosages at first, subsequently increasing the dose untila maximum response is obtained. Suitable dosages for administration inthe treatment or prevention of hypertension will ordinarily rangebetween about 1.0 to 50 mg/kg up to a maximum of about 200 mg/kg.

The compounds of Formula I can also be administered as pharmacologicallyacceptable acid addition salts such as the hydrochloride, hydrobromide,hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate,malate, succinate, tartrate and the like. Additionally, the compounds ofthis invention may be administered in a suitable hydrated form.

The compounds of this invention may be prepared by any number of methodsknown to those skilled in the art. For example, the particular sequenceof reactions by which the individual amino acids are joined to form thecompounds of Formula I is generally not of critical importance, beingchosen principally for convenience or for maximum yields. Moreover, thechoice of activating reagents and conditions for joining amino acids orsmall peptides is not limited to those specifically described herein.Peptide intermediates and products of this invention are typicallypurified by crystallization, where possible, or by columnchromatography. Furthermore, where racemic amino acid starting materialsare employed, intermediates and products may be separated during columnchromatography into diastereomers. For example, reaction ofracemic-t-butoxycarbonyl-2,6-dimethyl(D,L) tyrosine with a peptideintermediate results in racemic mixtures of diastereomeric products.Based upon thin layer chromatography results, these diastereomers arecomprised of a slow moving isomer (S) and a faster moving isomer (F). Indescribing these isomers herein, the assumption is made that the slowmoving diastereomer (S) corresponds to the L-isomer and the fast movingdiasteriomer (F) corresponds to the D-isomer form of the tyrosylstarting material.

The accompanying Charts are used to illustrate one of the possiblemethods used to prepare the compounds of this invention.

Chart A illustrates a general method for forming dipeptide intermediatesuseful in the synthesis of compounds of Formula I. Partially blockedamino acids of Formula XI, in which B represents common N-protectinggroups such as t-butoxycarbonyl, may be activated by any of severalmethods known to those skilled in the art. The generally preferredmethod includes forming a mixed anhydride by reaction with an alkylchlorocarbonate in an unreactive solvent containing a tertiary amine.Preferred conditions include cooling a mixture of the appropriatecompound of Formula XI in cold (ca. -30° to -40°) dimethylformamide ordichloromethane containing N-methylmorpholine, followed by addition ofisobutyl chloroformate. Once the mixed anhydride of Formula XII(X=OCOOCH₂ CH(CH₃)₂) has formed, the appropriate amine of Formula XIIIis added and the reaction allowed to proceed at room temperature, givingthe fully blocked intermediates of Formula XIV.

Especially where the amine of Formula XIII is N-substituted (i.e., whereR₅ is not hydrogen), an alternative method of activation involvingcarbodiimides may be more appropriate. For this method, compounds ofFormulas XI and XIII are stirred together in an unreactive solvent towhich is then added the carbodiimide. Preferred conditions includereaction in dichloromethane using dicyclohexylcarbodiimide. The isolatedintermediates, Formula XIV, are exactly the same as those formed by themixed anhydride method.

Using methods appropriate for the particular protecting groups B,compounds of Formula XIV may readily be deprotected to give compoundsXV. Where the t-butoxycarbonyl protecting group is employed, forexample, preferred deblocking conditions include acid solvolysis inhydrogen chloride/dioxane. Typically, the resultant hydrochloride saltsmay be used in subsequent reactions without first isolating the freeamine.

Chart B illustates one method for extending the peptide chain to formintermediates of Formula XXVII. Using methods described above (see alsoChart A), fully N-deprotected intermediates of Formula XXIV are formedfrom N-protected amino acids, Formula XXI, and omega-amino esters,Formula XXIII. Hydrolysis of these intermediates, Formula XXIV, affordsthe analogous acids of Formula XXV. Preferred hydrolysis conditionsinclude approximately molar sodium hydroxide in aqueous methanol,followed by neutralization with sodium bisulfate. Using the methodsdescribed above, compounds of Formula XXV are activated and then coupledwith intermediates of Formula XV to form N-(or)deprotected peptides ofFormula XXVI. As described above (see Chart A), removal of theprotecting groups B affords amino compounds of Formula XXVII.

Chart C illustrates one method for completing the extension of thepeptide chains. As described before (see Charts A and B), suitablyprotected aromatic amino acids of Formula XXXI are activated, forexample by using mixed anhydride or carbodiimide methods, and allowed toreact with intermediates of Formula XXVII. Appropriate removal ofprotecting groups from compounds XXXII affords compounds of thisinvention, Formula I.

Chart D illustrates one method for preparing sulfoxide or sulfonemembers of this invention, Formula XLII (i.e., Formula I where R=CH₂ CH₂S(O)CH₃ or R=CH₂ CH₂ SO₂ -CH₃, respectively), which for practicalreasons are generally prepared after the methionine-containing peptidesof Formula XLI have been fully formed using methods described above.Preferred oxidizing conditions include hydrogen peroxide in aqueousmethanol--at room temperature, sulfoxides are the predominant or soleoxidation product, whereas at elevated temperatures (e.g., refluxingsolvent), sulfones are formed.

The invention will appear more fully from the examples which follow.These examples are given by way of illustration only, and are not to beconstrued as limiting the invention either in spirit or in scope, asmany modifications both in materials and in methods will be apparentfrom this disclosure to those skilled in the art.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1t-butoxycarbonyl-N-(5-methoxy-5-oxopentyl)-L-phenylalaninamide

To a cold (ca -30° ), stirred solution of 26.5 g (0.1 mole) oft-butoxycarbonylphenylalanine (BOC-Phe) and 11.2 g (0.1 mole) ofN-methylmorpholine in 150 ml of dimethylformamide (DMF) was addeddropwise 13.2 ml (0.1 mole) of isobutylchloroformate. After warming andthen holding the temperature at ca. -15° for about ten minutes, thesolution was recooled to ca. -39°. To the cold mixture was addedadditional N-methylmorpholine (12.3 ml, ca. 0.11 mole), followed by 18.5g (0.11 mole) of methyl 5-aminopentanoate hydrochloride. The mixture wasallowed to warm to room temperature and to stand overnight. Solvent andother volatiles were removed by concentration in vacuo. The residue wastriturated with ethyl acetate, which was then washed successively withwater, 0.5M potassium bisulfate, water, and again with 0.5M potassiumbisulfate, and then dried over magnesium sulfate, filtered, andconcentrated to a white solid. After collection, the white solid waswashed thoroughly with Skellysolve B to give 36.4 g of the titlecompound, m.p. 98°-100°. Recrystallization from ethylacetate/Skellysolve B afforded analytically pure crystals.

Analysis. Calcd. For C₂₀ H₃₀ N₂ O₅ : C, 63.47; H, 7.99; N, 7.40. Found:C, 63.32; H, 8.03; N, 7.24.

Example 2 t-butoxycarbonyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamide

The title compound was prepared by the method of Example 1 using methyl6-aminohexanoate hydrochloride and was used in subsequent reactionswithout further purification.

Example 3 N-(6-methoxy-6-oxohexyl)-L-phenylalaninamide monohydrochloride

To a solution of the title compound of Example 2 (43.1 g, 0.11 mole) in100 ml of dioxane was added 100 ml of 6M hydrogen chloride/dioxane.After about 30 min. the solution was concentrated in vacuo to drynessand the residue triturated thoroughly with diethyl ether. The solid wascollected and washed well with diethyl ether, giving 34.7 g of the titlecompound, which was used in subsequent reactions without furtherpurification.

Example 4 N-(4-methoxy-4-oxobutyl)-L-phenylalaninamide monohydrochloride

The title compound was prepared by the methods of Examples 1 and 3 usingmethyl 4-aminobutanoate hydrochloride and was used in subsequentreactions without further purification.

Example 5 N-(5-methoxy-5-oxopentyl)-L-phenylalaninamidemonohydrochloride

The title compound was prepared by the method of Example 3 using thetitle compound of Example 1 and was used in subsequent reactions withoutfurther purification.

Example 6 N-(7-methoxy-7-oxoheptyl)-L-phenylalaninamidemonohydrochloride

The title compound was prepared by the methods of Examples 1 and 3 usingmethyl 7-aminoheptanoate hydrochloride and was used in subsequentreactions without further purification.

Example 7 N-(8-methoxy-8-oxooctyl)-L-phenylalaninamide monohydrochloride

The title compound was prepared by the methods of Examples 1 and 3 usingmethyl 8-aminooctanoate hydrochloride and was used in subsequentreactions without further purification.

Example 8 t-butoxycarbonyl-D-methionylglycine methyl ester

The title compound was prepared by the general method of Example 1 using24.9 g (0.1 mole) of t-butoxycarbonyl-D-methionine (BOC-D-Met) and 13.8g (0.11 mole) of glycine methyl ester hydrochloride. The crude productwas recrystallized from ethyl acetate/Skellysolve B to give the titlecompound, which was used in subsequent reactions without furtherpurification.

Example 9 t-butoxycarbonyl-D-methionylglycine

The title compound of Example 8 (32.0 g, 0.1 mole) was dissolved in 200ml of methanol to which was added 200 ml of 2M potassium hydroxide.After ca. 5 min. at room temperature the solution was concentrated toabout half volume and diluted with ethyl acetate. The solution wasneutralized by washing with two portions of 0.5M potassium bisulfate,and then dried over magnesium sulfate, filtered, and concentrated invacuo. The crude product was recrystallized to give the title compound,which was used in subsequent reactions without further purification.

Example 10t-butoxycarbonyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamide

A mixture of the title compounds of Example 3 (28.9 g, 0.088 mole) andExample 9 (27.2 g, 0.084 mole) in 150 ml of dichloromethane wassolubilized by warming and adding 9.8 ml (ca. 0.087 mole) ofN-methylmorpholine. After the solution was cooled to ca. 0° , 18.2 g(0.088 mole) of dicyclohexylcarbodiimide in 50 ml of dichloromethane wasadded, and the reaction mixture was allowed to warm to room temperature.After a total of four hours, insolubles were removed by filtration andthe filtrate was washed sequentially with two portions of 0.5M potassiumbisulfate. The organic phase was dried over magnesium sulfate, filtered,and concentrated in vacuo. The crude material was purified by columnchromatography on silica gel to give the title compound (42.0 g).

Analysis. Calcd. for C₂₈ H₄₄ N₄ O₇ S: C, 57.91; H, 7.64; N, 9.65; S,5.52. Found: C, 57.84; H, 7.75; N, 9.89; S, 5.55.

Example 11D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate

The title compound of Example 10 (12.0 g) was dissolved in 50 ml ofdioxane to which was added 50 ml of 6M hydrogen chloride/dioxane. Afterabout one hour, the volatiles were removed in vacuo and the residuetriturated thoroughly with diethyl ether. The title compound (10.9 g)was collected as an analytically pure hydrochloride hemihydrate.

Analysis. Calcd. for C₂₃ H₃₆ N₄ O₅ S.HCl.1/2H₂ O: C, 52.51; H, 7.28; N,10.65; S, 6.09; Cl, 6.74. Found: C, 52.33; H, 7.24; N, 10.68; S, 6.14;Cl, 6.69.

Example 12 t-butoxycarbonyl-2,6-dimethyltyrosine

To a stirred solution of 100 g (820 mmole) of 3,5-dimethylphenol and 79g (1 mole) of pyridine in 300 ml of cooled (5°-10°) toluene was slowlyadded 109 g (1 mole) of ethyl chloroformate in 100 ml of toluene. Afterovernight stirring, the mixture was concentrated in vacuo to an oilwhich was purified by distillation at reduced pressure, giving anintermediate carbonate diester. After heating 250 ml of concentratedhydrochloric acid to ca. 55°, 22 g of 37% aqueous formaldehyde wasadded, followed by addition of the carbonate diester. Hydrogen chloridegas was bubbled through the solution for about six hours. The mixturewas allowed to stand overnight at room temperature and then shaken withdichloromethane. The organic phase thus formed was washed with water,aqueous sodium bicarbonate, and saturated brine, and then dried oversodium sulfate, filtered, and concentrated in vacuo. The resultant4-chloromethyl derivative was purified by distillation at reducedpressure. After preparing an ethanolic solution of sodium ethoxide from2.5 g (110 mmole) of sodium metal, 21.7 g (100 mmole) of diethylacetamidomalonate was added and the solution heated to reflux. Anethanolic solution of the 4-chloromethyl intermediate was then added andthe mixture was heated at reflux for another 2.5 hours. After standingovernight at room temperature, the mixture was treated with 6.6 g (110mmole) of acetic acid. The resultant gum was dissolved indichloromethane, which was then washed with aqueous sodium bicarbonate,filtered, and concentrated in vacuo to an oily residue.Recrystallization from diethyl ether afforded 6.5 g of the benzylmalonate derivative (from which the O-ethyoxycarbonyl group was lost).Heating a 1.0 g portion of the malonate derivative in concentratedhydrochloric acid at 95° for about three days afforded 680 mg of2,6-dimethyltyrosine as the nearly analytically pure hydratedhydrochloride salt. [Analysis. Calcd. for C₁₁ H₁₅ NO₃.HCl.H₂ O: C,50.09; H, 6.13; N, 5.31; Cl, 13.44. Found: C, 49.36; H, 6.30; N, 5.20;Cl, 14.10.]About 45 g of the amino acid prepared as above was thendissolved in ca. 400 ml of ice water, which was adjusted to about pH 10.Di-t-butyl dicarbonate (41 g) was added, with maintenance of pH to 13 tosaponify O-butoxycarbonyl groups, the mixture was cooled to about 0° andadjusted to pH 2. The crude title compound was extracted into ethylacetate, which was washed with saturated brine, dried over sodiumsulfate, filtered, and dried under a stream of nitrogen.Recrystallization from ethyl acetate afforded analytically pureBOC-protected compound.

Analysis. Calcd. for C₁₆ H₂₃ NO₅ : C, 62.12; H, 7.49; N, 4.53. Found: C,61.87; H, 7.51; N, 4.34.

Example 13 t-butoxycarbonyl-2,6-dimethyl-(D andL)-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamide

The title compound was prepared by the method of Example 1 using 6.80 g(0.022 mole) of t-butoxycarbonyl-2,6-dimethyltyrosine and the titlecompound of Example 11 (10.8 g, 0.020 mole). A portion of the cruderacemic product (4.5 g) was purified by column chromatography on silicagel (methanol/chloroform eluent) to give 1.79 g of the D isomer and 2.11g of the L isomer. The individual isomeric components, differing in thealpha-carbon stereochemistry of the 2,6-dimethyltyrosine moiety, wereused without further purification in subsequent reactions.

Example 142,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36739)

The L isomer of the title compound of Example 13 (2.11 g) was dissolvedin 20 ml of acetic acid to which was added 20 ml of 6M hydrogenchloride/dioxane. After one hour at room temperature, volatiles wereremoved in vacuo and the residue triturated thoroughly with diethylether. The title compound was collected as 1.95 g of an analyticallypure solid.

[α]_(D) +5.3°; [α]₃₆₅ +187.8° (methanol)

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₇ S.HCl.H₂ O: C, 56.23; H, 7.22; N,9.64; S, 4.41; Cl, 4.88. Found: C, 56.19; H, 7.04; N, 9.57; S, 4.33; Cl,4.99.

Example 152,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36738)

The title compound was prepared by the method of Example 14 using the Disomer of Example 13.

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₇ S.HCl.H₂ O: C, 56.23; H, 7.22; N,9.64; S, 4.41; Cl, 4.88. Found: C, 56.19; H, 7.04; N, 9.57; S, 4.33; Cl,4.99. [α]_(D) -51.1°; [α]₃₆₅

Example 162,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride 21/2 hydrate (SC-36755)

To a solution of the title compound of Example 14 (0.71 g, 1.0 mmole) in3.5 ml of water and 3.5 ml of methanol was added 0.5 ml of 10M hydrogenperoxide. After one hour at room temperature, the reaction was dilutedwith water to about 70 ml, filtered, and the filtrate lyophilized. Thetitle compound (0.68 g) was isolated as an analytically pure hydratedsolid.

[α]_(D) +46.7°; [α]₃₆₅ +172.0° (methanol)

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₈ S.HCl.21/2H₂ O: C, 53.08; H, 7.20; N,9.10; S, 4.17; Cl, 4.61. Found: C, 52.78; H, 6.57; N, 8.95; S, 4.35; Cl,4.70.

Example 172,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride 21/2 hydrate (SC-36773)

The title compound was prepared by the method of Example 16 using thetitle compound of Example 15.

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₈ S.HCl.21/2H₂ O: C, 53.08; H, 7.20; N,9.10; S, 4.17; Cl, 4.61. Found: C, 52.96; H. 6.71; N, 9.04; S, 4.24; Cl,4.55.

Example 182,6-dimethyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-34973)

The title compound was prepared from an unresolved mixture of thecompound mixture of Example 13 using the methods of Examples 14 and 16.

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₈ S.HCl.3/2H₂ O: C, 54.35; H, 7.11; N,9.32; S, 4.27; Cl, 4.72. Found: C, 54.20; H, 6.80; N, 9.23; S, 4.17; Cl,4.70.

Example 192,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(5-methoxy-5-oxopentyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36589)

The title compound was prepared by the methods of Examples 10, 11, 13,and 14 using the title compound of Example 5.

Analysis. Calcd. for C₃₃ H₄₇ N₅ O₇.HCl.H₂ O: C, 55.65; H, 7.08; N, 9.83;S, 4.50; Cl, 4.98. Found: S, 56.00; H, 7.06; N, 9.61; S, 4.09; Cl, 5.01.

Example 202,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(5-methoxy-5-oxopentyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36588)

The title compound was prepared by the methods of Examples 10, 11, 13,and 15 using the title compound of Example 5.

Analysis. Calcd. for C₃₃ H₄₇ N₅ O₇ S.HCl.H₂ O; C, 55.65; H, 7.08; N,9.83; S, 4.50; Cl, 4.98. Found: C, 55.84; H, 7.03; N, 9.77; S, 4.43; Cl,5.21.

Example 212,6-dimethyl-L-tyrosyl-[4-methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(5-methoxy-5-oxopentyl)-L-phenylalaninamidemonohydrochloride 21/2 hydrate (SC-36655)

The title compound was prepared by the method of Example 16 using thetitle compound of Example 19.

Analysis. Calcd. for C₃₃ H₄₇ N₅ O₈ S.HCl.21/2H₂ O: C, 52.48; H, 4.07; N,9.27; S, 4.25; Cl, 4.69. Found: C, 52.31; H, 6.58; N, 9.16; S, 4.30.

Example 222,6-dimethyl-D-tyrosyl-[4-methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(5-methoxy-5-oxopentyl)-L-phenylalaninamidemonohydrochloride

The title compound is prepared by the method of Example 16 using thetitle compound of Example 20.

Example 232,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(7-methoxy-7-oxoheptyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36777)

The title compound was prepared by the methods of Examples 10, 11, 13,and 14 using the title compound of Example 6.

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₇ S.HCl.H₂ O: C, 56.78; H, 7.35; N,9.46; S, 4.33; Cl, 4.79. Found: C, 56.84; H, 7.07; N, 9.60.

Example 242,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(7-methoxy-7-oxoheptyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36776)

The title compound was prepared by the methods of Examples 10, 11, 13,and 15 using the title compound of Example 6.

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₇ S.HCl.1/2H₂ O: C, 57.48; H, 7.30; N,9.58; S, 4.38; Cl, 4.85. Found: C, 57.36; H, 7.11; N, 9.61.

Example 252,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(7-methoxy-7-oxoheptyl)-L-phenylalaninamidemonohydrochloride (SC-36922)

The title compound was prepared by the method of Example 16 using thetitle compound of Example 23.

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₈ S.HCl: C, 54.93; H, 7.24; N, 9.15; S,4.19. Found: C, 54.96; H, 6.96; N, 9.17; S, 4.19.

Example 262,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(7-methoxy-7-oxoheptyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-36921)

The title compound was prepared by the method of Example 16 using thetitle compound of Example 24.

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₈ S.HCl.3/2H₂ O: C, 54.93; H, 7.24; N,9.15; S, 4.19; Cl, 4.63. Found: C, 54.57; H, 6.92; N, 9.08; S, 3.83.

Example 272,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(8-methoxy-8-oxooctyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36338)

The title compound was prepared by the method of Examples 10, 11, 13,and 14 using the title compound of Example 7.

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl.1/2H₂ O: C, 58.01; H, 7.44; N,9.40; S, 5.41. Found: C, 57.85; H, 7.68; N, 9.40; S, 5.22.

Example 282,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(8-methoxy-8-oxooctyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36337)

The title compound was prepared by the methods of Examples 10, 11, 13,and 15 using the title compound of Example 7.

Analysis Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl.H₂ O: C, 57,32; H, 7.48; N,9.28; Cl, 4.70. Found: C, 57.33; H, 7.51; N, 9.13; Cl, 5.41.

Example 292,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(8-methoxy-8-oxooctyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36344)

The title compound was prepared by the methods of Example 15 using thetitle compound of Example 27.

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₈ S.HCl.H₂ O: C, 56.13; H, 7.33; N,9.09; Cl, 4.60. Found: C, 56.04; H, 7.22; N, 9.06, Cl, 4.81.

Example 302,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(8-methoxy-8-oxooctyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36392)

The title compound was prepared by the method of Example 16 using thetitle compound of Example 28.

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₈ S.HCl.H₂ O: C, 56.13; H, 7.33; N,9.09. Found: C, 55.76; H, 7.18; N, 9.02.

Example 312,6-dimethyltyrosyl-[4-(methylsufinyl)-D-2-aminobutanoyl]glycyl-N-(4-methoxy-4-oxobutyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-34972)

The title compound was prepared by the methods of Examples 10, 11, 13(except that the racemic mixture was not resolved), 14, and 16 using thetitle compound of Example 4.

Analysis. Calcd. for C₃₂ H₄₅ N₅ O₈ S.HCl.3/2H₂ O: C, 53.14; H, 6.83; N,9.68; S, 4.43; Cl, 4.90. Found: C, 53.27; H, 6.55; N, 9.34; S, 4.42; Cl,5.37.

Example 32L-tyrosyl-D-methionylgycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-36798)

The title compound was prepared using the methods of Examples 13 and 14using t-butoxycarbonyltyrosine in place oft-butoxycarbonyl-2,6-dimethyltyrosine. Structure assignment wassupported by elemental analysis.

Analysis. Calcd. for C₃₂ H₄₅ N₅ O₇ S.HCl.3/2H₂ O: C, 54.34; H, 6.98; N,9.90; S, 4.53; Cl, 5.01. Found: C, 54.30; H, 6.61; N, 9.82; S, 4.19; Cl,5.61.

Example 33L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-36801)

The title compound was prepared by the method of Example 16 using thetitle product of Example 32. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₂ H₄₅ N₅ O₈ S.HCl.H₂ O: C, 53.81; H, 6.77; N,9.81; S, 4.49; Cl, 5.21. Found: C, 53.46; H, 6.55; N, 9.80; S, 4.23; Cl,5.21.

Example 34 N.sup.α-methyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36814)

The title compound was prepared using the methods of Examples 13 and 14using t-butoxycarbonyl-N-methyltyrosine in place oft-butoxycarbonyl-2,6-dimethyltyrosine. Structure assignment wassupported by elemental analysis.

Analysis. Calcd. for C₃₃ H₄₇ N₅ O₇ S.HCl.H₂ O: C, 56.36; H, 7.02; N,9.96; S, 4.07; Cl, 5.04. Found: C, 56.21; H, 6.90; N, 9.81; S, 4.47; Cl,5.14.

Example 35Nα-methyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride 11/4 hydrate (SC-36816)

The title compound was prepared by the method of Example 16 using thetitle product of Example 34. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₃ H₄₇ N₅ O₈ S.HCl.1/4H₂ O: C, 54.09; H, 6.95; N,9.56; S, 4.37; Cl, 4.84. Found: C, 53.96; H, 6.69; N, 9.53; S, 4.26; Cl,4.95.

Example 36 t-butoxycarbonyl-2,4,6-trimethylphenylalanine

After preparing an ethanolic solution of sodium ethoxide from 30.1 g(1.31 mole) of sodium metal, 200 g (1.19 mole) of diethylacetamidomalonate was added and the solution heated to reflux. Anethanolic solution of the 2,4,6-trimethylbenzyl chloride was then addedand the mixture was heated at reflux for another four hours. The mixturewas concentrated in vacuo and the residue triturated multiply withwater, then with dichloromethane. After removing insolubles byfiltration, the filtrate was washed with brine, decolorized withactivated carbon, filtered, concentrated to a small volume, and allowedto stand. Repetition of the decolorization, followed byrecrystallization from Skellysolve B afforded the analytically purebenzyl malonate derivative. A portion of the malonate (12 g, 36 mmole)was heated at reflux in a mixture of 50 ml ethanol and 50 mlconcentrated hydrochloric acid for about four days. Upon cooling,racemic 2,4,6-trimethylphenylalanine precipitated. The BOC-protectedtitle compound was prepared using di-t-butyl dicarbonate as described inExample 12.

Example 372,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-2,4,6-trimethylphenylalaninamidemonohydrochloride monohydrate (SC-39724)

After preparingN-(6-methoxy-6-oxohexyl)-2,4,6-trimethylphenylalaninamidemonohydrochloride from the title product of Example 36 by the methods ofExamples 1 and 3, the title compound was prepared by the methodsdescribed in Examples 10, 11, 13, and 14. Structure assignment wassupported by elemental analysis.

Analysis. Calcd. for C₃₇ H₅₅ N₅ O₇ S.HCl.H₂ O: C, 57.84; H, 7.61; N,9.11; S, 4.17; Cl, 4.61. Found: C, 58.12; H, 7.55; N, 8.96; S, 4.13; Cl,5.07.

Example 382,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-2,4,6-trimethylphenylalaninamidemonohydrochloride hemihydrate (SC-39699)

The title compound was prepared by the methods summarized in Example 37,except for using the method of Example 15 instead of Example 14.Structure assignment was supported by elemental analysis.

Analysis. Calcd. for C₃₇ H₅₅ N₅ O₇ S.HCl.1/2H₂ O: C, 58.52; H, 7.57; N,9.22; S, 4.22; Cl, 4.67. Found: C, 58.44; H, 7.58; N, 8.88; S, 4.19; Cl,4.94.

Example 392,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-2,4,6-trimethylphenylalaninamidemonohydrochloride sesquihydrate (SC-40178)

The title compound was prepared by the method of Example 16 using thetitle product of Example 37. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₇ H₅₅ N₅ O₈ S.HCl.3/2H₂ O: C, 56.01; H, 7.50; N,8.83; S, 4.04; Cl, 4.47. Found: C, 55.84; H, 7.20; N, 8.80; S, 4.01; Cl,4.56.

Example 402,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-2,4,6-trimethylphenylalaninamidemonohydrochloride sesquihydrate (SC-40075)

The title compound was prepared by the method of Example 16 using thetitle product of Example 38. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₇ H₅₅ N₅ O₈ S.HCl.3/2H₂ O: C, 56.01; H, 7.50; N,8.83; S, 4.04; Cl, 4.47. Found: C, 56.23; H, 7.32; N, 8.78; S, 4.16; Cl,4.60.

Example 412,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(6-hydroxyhexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-39782)

Using 6-aminohexanol instead of an omega-aminoalkanoic acid,t-butoxycarbonyl-N-(6-hydroxyhexyl)-L-phenylalaninamide was prepared bythe general method of Example 1. Using the method of Example 3, exceptfor adding about an equal volume of acetic acid to facilitate solution,the N-protected precursor was converted toN-(6-acetyloxyhexyl)-L-phenylalaninamide. After then proceeding by themethods of Examples 10, 11, and 13, the intermediate terminal O-acetylgroup was removed by the method of Example 9. Finally, the titlecompound was prepared using the method of Example 11. Structureassignment was supported by elemental analysis.

Analysis. Calcd. for C₃₃ H₄₉ N₅ O₆ S.HCl.H₂ O: C, 56.76; H, 7.50; N,10.03; S, 4.59; Cl, 5.08. Found: C, 56.57; H, 7.50; N, 9.74; S, 4.45;Cl, 5.39.

Example 422,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(6-hydroxyhexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-39781)

The title compound was prepared by the methods summarized in Example 41,except for using the method of Example 15 instead of Example 11 in thefinal step. Structure assignment was supported by elemental analysis.

Analysis. Calcd. for C₃₃ H₄₉ N₅ O₆ S.HCl.H₂ O: C, 56.76; H, 7.50; N,10.03; S, 4.59; Cl, 5.08. Found: C, 56.40; H, 7.48; N, 9.75; S, 4.41;Cl, 5.53.

Example 432,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-hydroxyhexyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-40238)

The title compound was prepared by the method of Example 16 using thetitle product of Example 41. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₃ H₄₉ N₅ O₇ S.HCl/3/2H₂ O: C, 54.87; H, 7.26; N,9.70; S, 4.44; Cl, 4.91. Found: C, 54.57; H, 6.76; N, 9.41; S, 4.30; Cl,5.12.

Example 442,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-hydroxyhexyl)-L-phenylalaninamidemonohydrochloride dihydrate (SC-40192)

The title compound was prepared by the method of Example 16 using thetitle product of Example 42. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₃ H₄₉ N₅ O₇ S.HCl.2H₂ O: C, 54.12; H, 7.43; N,9.56; S, 4.38; Cl, 4.84. Found: C, 54.32; H, 6.79; N, 9.47; S, 4.31; Cl,5.17.

Example 452,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(6-acetyloxyhexyl)-N.sup.α-methyl-L-phenylalaninamide monohydrochloride hemihydrate (SC-39745)

The title compound was prepared by the methods summarized in Example 41,except that t-butoxycarbonyl-N-methyl-L-phenylalanine was used insteadof t-butoxycarbonylphenylalanine and the O-acetyl group was not removedbefore proceeding to the final reaction, which employed the method ofExample 14. Structure assignment was supported by elemental analysis.

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl.1/2H₂ O: C, 58.01; H, 7.30; N,9.40; S, 4.30; Cl, 4.76. Found: C, 57.67; H, 7.21; N, 9.33; S, 4.46; Cl,5.10.

Example 462,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(6-acetyloxyhexyl)-N.sup.α-methyl-L-phenylalaninamide monohydrochloride monohydrate (SC-39734)

The title compound was prepared by the methods of Example 45, except forusing the method of Example 15 instead of Example 14 in the final step.Structure assignment was supported by elemental analysis.

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl.H₂ O: C, 57.32; H, 7.48; N,9.28; S, 4.25; Cl, 4.70. Found: C, 57.26; H, 7.24; N, 9.20; S, 4.30; Cl,5.17.

Example 472,6-dimethyl-L-tyrosyl-D-methionylglycyl-N-(6-hydroxyhexyl)-N.sup.α-methyl-L-phenylalaninamide hydrochloride monohydrate (SC-40061)

The title compound was prepared (as the 1.2 HCl monohydrate) from thetitle product of Example 45 using the method of Example 9. Structureassignment was supported by elemental analysis.

Analysis. Calcd. for C₃₄ H₅₁ N₅ O₆ S.1.2HCl.H₂ O: C, 56.75; H, 7.59; N,9.73; S, 4.46; Cl, 5.91. Found: C, 56.83; H, 7.38; N, 9.40; S, 4.36; Cl,5.74.

Example 482,6-dimethyl-D-tyrosyl-D-methionylglycyl-N-(6-hydroxyhexyl)-N.sup.α-methyl-L-phenylalaninamide hydrochloride monohydrate (SC-40060)

The title compound was prepared (as the 1.2 HCl monohydrate) from thetitle product of Example 45 using the method of Example 9. Structureassignment was supported by elemental analysis.

Analysis. Calcd. for C₃₄ H₅₁ N₅ O₆ S.1.2HCl.H₂ O: C, 56.75; H, 7.59; N,9.73; S, 4.46; Cl, 5.91. Found: 56.77; H, 7.37; N, 9.49; S, 4.45; Cl,5.74.

Example 492,6-dimethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-hydroxyhexyl)-N.sup.α-methyl-L-phenylalaninamide monohydrochloride sesquihydrate (SC-40446)

The title compound was prepared by the method of Example 16 using thetitle product of Example 47. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₄ H₅₁ N₅ O₇ S.HCl.3/2H₂ O: C, 55.38; H, 7.52; N,9.50; S, 4.35; Cl, 4.81. Found: C, 55.38; H, 7.23; N, 9.16; S, 4.26; Cl,5.14.

Example 502,6-dimethyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-hydroxyhexyl)-N.sup.α-methyl-L-phenylalaninamide monohydrochloride dihydrate (SC-40358)

The title compound was prepared by the method of Example 16 using thetitle product of Example 48. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₄ H₅₁ N₅ O₇ S.HCl.2H₂ O: C, 54.72; H, 7.56; N,9.38; S, 4.30; Cl, 4.75. Found: C, 54.86; H, 7.48; N, 9.46; S, 4.29; Cl,5.00.

Example 51 t-butoxycarbonyl-N-ethyl-L-tyrosine

To a stirred mixture of 18.6 g (50 mmole) oft-butoxycarbonyl-O-benzyl-L-tyrosine in 400 ml of freshly driedtetrahydrofuran cooled to -78° was added dropwise 58 ml of 1.9M t-butyllithium in pentane. After warming to -20°, the solution was stirred for1.5 hours, and 9.5 g (50 mmole) of triethyloxonium fluoborate was thenadded. After about one hour the mixture was poured into and shaken withaqueous sodium bisulfate (giving a pH of 3 in the aqueous phase). Theaqueous phase was washed with water, dried over sodium sulfate,filtered, and concentrated in vacuo to an oil. Purification by columnchromatography on silica gel afforded 12.6 g of the O-benzyl etherderivative of the title compound as a white solid. [Analysis. Calcd. forC₂₃ H₂₉ NO₅ : C, 69.15; H, 7.32; N, 3.51. Found: C, 68.70; H, 7.22; N,3.53.] A portion (1.0 g, 2.25 mmole) of the benzyl ether intermediate in35 ml of tetrahydrofuran was hydrogenated at room temperature usinghydrogen gas at atmospheric pressure and 5% palladium on carbon ascatalyst. After filtration the filtrate was concentrated to dryness andpurified by column chromatography, giving the analytically pure titlecompound.

[α]_(D) -124.4°; [α]₃₆₅ -447.8° (chloroform)

Analysis. Calcd. for C₁₆ H₂₃ NO₅ : C, 62.12; H, 7.49; N, 4.53. Found: C,62.14; H, 7.81; N, 4.73.

EXAMPLE 52 t-butoxycarbonyl-N.sup.α-ethyl-O-(2-methylpropoxycarbonyl)-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamide

The title compound was prepared from 2.09 g (6.8 mmole) of the titleproduct of Example 51 using the general method described in Example 13(and Example 1) except that a two-fold quantity (1.77 ml, ca. 13.5mmole) of isobutylchloroformate was employed. Purification by columnchromatography on silica gel afforded 3.75 g of the title compound as ananalytically pure glassy solid.

Analysis. Calcd. for C₄₄ H₆₅ N₅ O₁₁ S: C, 60.60; H, 7.51; N, 8.03; S,3.68. Found: C, 60.55; H, 7.55; N, 8.02; S, 3.68.

Example 53 N.sup.α-ethyl-O-(2-methylpropoxycarbonyl)-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride (SC-36763)

The title compound was prepared by the method of Example 14 using 1.7 g(1.9 mmole) of the title product of Example 52. Structure assignment wassupported by elemental analysis.

[α]_(D) +36.0; [α]₃₆₅ +132.0 (methanol)

Analysis. Calcd. for C₃₉ H₅₇ N₅ O₉ S.HCl: C, 57.94; H, 7.23; N, 8.66; S,3.97; Cl, 4.38. Found: C, 57.79; H, 7.13; N, 8.77; S, 4.06; Cl, 4.46.

Example 54 N.sup.α-ethyl-O-(2-methylpropoxycarbonyl)-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride (SC-36792)

The title compound was prepared by the method of Example 16 using thetitle product of Example 53. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₉ H₅₇ N₅ O₁₀ S.HCl: C, 56.82; H, 7.09; N, 8.50;S, 3.89; Cl, 4.30. Found: C, 56.88; H, 6.98; N, 8.48; S, 3.99; Cl, 4.40.

Example 55 t-butoxycarbonyl-N.sup.α-ethyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36821)

To a stirred mixture of 1.7 g (1.9 mmole) of the title product ofExample 52 in 40 ml of methanol was added 10 ml of 10% aqueous potassiumcarbonate. After about 75 minutes the resultant solution was poured intoa mixture of 150 ml of dichloromethane and 100 ml of 0.5M potassiumbisulfate. The organic phase (containing the crude neutralized product)was separated and the aqueous layer was further extracted withdichloromethane. The combined organic layers were concentrated todryness and purified by column chromatography, giving the analyticallypure BOC-protected derivative of the title compound. [Analysis. Calcd.for C₃₉ H₅₇ N₅ O₉ S: C, 60.68; H, 7.44; N, 9.07; S, 4.15. Found: C,60.64; H, 7.52; N, 8.90; S, 4.01.] The intermediate thus formed wasconverted to the title compound by the method described in Example 14.Structure Assignment was supported by elemental analysis.

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₇ S.HCl.1/2H₂ O: C, 56.93; H, 7.17; N,9.77; S, 4.47; Cl, 4.94. Found: C, 56.98; H, 7.05; N, 9.82; S, 4.35; Cl,5.11.

Example 56 N.sup.α-ethyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36825)

The title compound was prepared by the method of Example 16 using thetitle product of Example 55. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₄ H₄₉ N₅ O₈ S.HCl.H₂ O: C, 55.68; H, 7.01; N,9.55; S, 4.37; Cl, 4.83. Found: C, 55.44; H, 6.87; N, 9.47; S, 4.23; Cl,4.99.

Example 57O-(2-methylpropoxycarbonyl)-2,3,6-trimethyltyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride trihydrate (SC-36874)

Using t-butoxycarbonyl-2,3,6-trimethyltyrosine prepared from2,3,5-trimethylphenol by the method of Example 12, the title compoundwas prepared by the methods of Examples 52 (basically the method ofExample 13 without resolution of the racemic mixture) and 14. Structureassignment was supported by elemental analysis.

Analysis. Calcd. for C₄₀ H₅₉ N₅ O₉ S.HCl.3H₂ O: C, 54.81; H, 7.58; N,7.99; S, 3.66; Cl, 4.04. Found: C, 54.87; H, 6.93; N, 8.07; S, 3.81; Cl,4.12.

Example 58O-(2-methylpropoxycarbonyl)-2,3,6-trimethyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride sesquihydrate (SC-36889)

The title compound was prepared by the method of Example 16 using thetitle product of example 57. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₄₀ H₅₉ N₅ O₁₀ S.HCl.3/2H₂ O: C, 56.02; H, 7.40; N,8.17; S, 3.74; Cl, 4.13. Found: C, 56.18; H, 7.14; N, 8.23; S, 3.80; Cl,4.11.

Example 592,3,6-trimethyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-37279)

Using t-butoxycarbonyl-2,3,6-trimethyltyrosine prepared from2,3,5-trimethylphenol by the method of Example 12, the title compoundwas prepared by the methods of Examples 52 (except that the racemicmixture was separated as in Example 13) and 55. Structure assignment wassupported by elemental analysis.

[α]_(D) +23.3+; [α]₃₆₅ +100.0° (methanol)

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₇ S.HCl.1/2H₂ O: C, 57.48; H, 7.30; N,9.58; S, 4.38; Cl, 4.85. Found: C, 57.13; H, 7.01; N, 9.50; S, 4.60; Cl,5.10.

Example 602,3,6-trimethyl-D-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-37277)

The title compound was prepared by the methods summarized in Example 59,except for using the isomer having 2,3,6-trimethyl-D-tyrosine. Structureassignment was supported by elemental analysis.

[α]_(D) -49.8°; [α]₃₆₅ -186.5° (methanol)

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₇ S.HCl.1/2H₂ O: C, 57.48; H, 7.30; N,9.58; S, 4.38; Cl, 4.85. Found: C, 57.13; H, 6.99; N, 9.49; S, 4.49; Cl,5.10.

Example 612,3,6-trimethyl-L-tyrosyl-[4-methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-37336)

The title compound was prepared by the method of Example 16 using thetitle product of Example 59. Structure assignment was supported byelemental analysis.

[α]_(D) +40.4°; [α]₃₆₅ +150.7° (methanol)

Analysis. Calcd. for C₃₅ H₅₁ N₅ O₈ S.HCl.H₂ O: C, 55.58; H, 7.19; N,9.26; S, 4.23; Cl, 4.69. Found: C, 55.60; H, 7.01; N, 9.26; S, 4.23; Cl,4.86.

Example 622,3,6-trimethyl-D-tyrosyl-[4-methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxo-hexyl)-L-phenylalaninamidemonohydrochloride monohydrate (SC-37334)

The title compound was prepared by the method of Example 16 using thetitle product of Example 60. Structure assignment was supported byelemental analysis.

[α]_(D) -46.2°; [α]₃₆₅ -166.2° (methanol)

Analysis. Calcd. for C35H₅₁ N₅ O₈ S.HCl.H₂ O: C, 55.58; H, 7.19; N,9.26; S, 4.23; Cl, 4.69. Found: C, 55.98; H, 7.01; N, 9.19; S, 4.23; Cl,5.14.

Example 63O-(2-methylpropoxycarbonyl)-2-methyltyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36886)

Using t-butoxycarbonyl-2-methyltyrosine prepared from 3-methylphenol bythe method of Example 12, the title compound was prepared by the methodsof Examples 52 (basically the method of Example 13 without resolution ofthe racemic mixture) and 14. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₈ H₅₅ N₅ O₉ S.HCl.1/2H₂ O: C, 56.80; H, 7.15; N,8.71; S, 3.99; Cl, 4.41. Found: C, 56.80; H, 7.05; N, 8.82; S, 4.09; Cl,4.47.

Example 64O-(2-methylpropoxycarbonyl)-2-methyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]-glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36899)

The title compound was prepared by the method of Example 16 using thetitle product of Example 63. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₈ H₅₅ N₅ O₁₀ S.HCl.H₂ O: C, 55.69; H, 7.01; N,8.55; S, 3.91; Cl, 4.33. Found: C, 55.53; H, 7.00; N, 8.73; S, 3.90; Cl,4.39.

Example 652-methyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride

Using t-butoxycarbonyl-2-methyltyrosine prepared from 3-methylphenol bythe method of Example 12, the title compound is prepared by the methodsof Examples 52 (except that the racemic mixture is separated as inExample 13) and 55.

Example 662-methyl-D-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride

The title compound is prepared by the methods summarized in Example 65,except for using the isomer having 2-methyl-D-tyrosine.

Example 672-methyl-L-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride

The title compound is prepared by the method of Example 16 using thetitle product of Example 65.

Example 682-methyl-D-tyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride

The title compound is prepared by the method of Example 16 using thetitle product of Example 66.

Example 69O-(2-methylpropoxycarbonyl)-3-t-butyl-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride (SC-36898)

Using t-butoxycarbonyl-3-t-butyltyrosine prepared from 2-t-butylphenolby the method of Example 12, the title compound was prepared by themethods of Examples 52 (basically the method of Example 13 withoutresolution of the racemic mixture) and 14. Structure assignment wassupported by elemental analysis.

Analysis. Calcd. for C₄₁ H₆₁ N₅ O₉ S.HCl: C, 58.87; H, 7.47; N, 8.37; S,3.83; Cl, 4.24. Found: C, 58.53; H, 7.52; N, 8.35; S, 3.79; Cl, 4.24.

Example 70O-(2-methylpropoxycarbonyl)-3-t-butyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36933)

The title compound was prepared by the method of Example 16 using thetitle product of Example 69. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₄₁ H₆₁ N₅ O₁₀ S.HCl.1/2H₂ O: C, 57.16; H, 7.37; N,8.13; S, 3.72; Cl, 4.11. Found: C, 57.12; H, 7.36; N, 8.13; S, 3.68; Cl,3.98.

Example 713-t-butyl-L-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride (SC-39926)

Using t-butoxycarbonyl-3-t-butyltyrosine prepared from 2-t-butylphenolby the method of Example 12, the title compound was prepared by themethods of Examples 52 (except that the racemic mixture was separated asin Example 13) and 55. Structure assignment was supported by elementalanalysis.

[α]_(D) +6.8°; [α]₃₆₅ +27.5° (methanol)

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl: C, 58.72; H, 7.39; N, 9.51.Found: C, 58.58; H, 7.39; N, 9.30.

Example 723-t-butyl-D-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride (SC-39913)

The title compound was prepared by the methods summarized in Example 52,except for using the isomer having 3-t-butyl-D-tyrosine. Structureassignment was supported by elemental analysis.

[α]_(D) -19.4°; [α]₃₆₅ -92.3° (methanol)

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₇ S.HCl: C, 58.72; H, 7.39; N, 9.51; S,4.35. Found: C, 58.47; H, 7.42; N, 9.52; S, 4.35.

Example 733-t-butyl-L-tyrosyl-[4-(methylsulfonyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-39983)

The title sulfone was prepared from the title product of Example 71using the method of Example 16, except that the methanolic hydrogenperoxide solution was heated at reflux for about one hour. Structureassignment was supported by elemental analysis.

[α]_(D) +14.2°; [α]₃₆₅ +60.4° (methanol)

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₉ S.HCl.1/2H₂ O: C, 55.62; H, 7.13; N,9.01. Found: C, 55.38; H, 7.29; N, 9.03.

Example 743-t-butyl-D-tyrosyl-[4-(methylsulfonyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-39967)

The title compound was prepared by the method of Example 73 using thetitle product of Example 72. Structure assignment was supported byelemental analysis.

[α]_(D) -16.0°; [α]₃₆₅ -64.9° (methanol)

Analysis. Calcd. for C₃₆ H₅₃ N₅ O₉ S.HCl.1/2H₂ O: C, 55.62; H, 7.13; N,9.01. Found: C, 55.20; H, 7.21; N, 9.00.

Example 752,4-dimethyl-3-(2-methylpropoxycarbonyloxy)-phenylalanyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36888)

Using t-butoxycarbonyl-2,4-dimethyl-3-hydroxyphenylalanine prepared from2,6-dimethylphenol by the method of Example 12, the title compound wasprepared by the methods of Examples 52 (basically the method of Example13 without the resolution of the racemic mixture) and 14. Structureassignment was supported by elemental analysis.

Analysis. Calcd. for C₃₉ H₅₇ N₅ O₉ S.HCl.1/2H₂ O: C, 57.30; H, 7.27; N,8.57; S, 3.92; Cl, 4.34. Found: C, 57.30; H, 7.18; N, 8.57; S, 3.96; Cl,4.30.

Example 762,4-dimethyl-3-(2-methylpropoxycarbonyloxy)-phenylalanyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-36917)

The title compound was prepared by the method of Example 16 using thetitle product of example 75. Structure assignment was supported byelemental analysis.

Analysis. Calcd. for C₃₉ H₅₇ N₅ O₁₀ S.HCl.2H₂ O: C, 54.44; H, 7.26; N,8.14; S, 3.73; Cl, 4.12. Found: C, 54.38; H, 6.77; N, 8.14; S, 3.78; Cl,4.12.

Example 772,4-dimethyl-3-hydroxyphenylalanyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride hemihydrate (SC-40367)

Using t-butoxycarbonyl-2,4-dimethyl-3-hydroxyphenylalanine prepared from2,6-dimethylphenol by the method of Example 12, the title compound wasprepared by the methods of Examples 52 (without the resolution of theracemic mixture) and 55. Structure assignment was supported by elementalanalysis.

Analysis. Calcd. for C₃₃ H₄₉ N₅ O₈ S.HCl.1/2H₂ O: C, 54.94; H, 7.13; N,9.71. Found: C, 54.84; H, 6.66; N, 9.26.

Example 782,6-dimethyl-L-tyrosyl-D-alanylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalanamidemonohydrochloride (SC-39865)

The title compound was prepared by the methods of Examples 8 (except forusing t-butoxycarbonyl-D-alanine instead oft-butoxycarbonyl-D-methionine), 9, 10, 11, 13 and 14. Structureassignment was supported by elemental analysis.

[α]_(D) +53.9°; [α]₃₆₅ +200° (methanol)

Analysis. Calcd. for C₃₂ H₄₅ N₅ O₇.HCl: C, 59.20; H, 7.30; N, 10.79.Found: C, 58.83; H, 7.14; N, 10.53.

Example 792,6-dimethyl-D-tyrosyl-D-alanylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalanamidemonohydrochloride hemihydrate (SC-39804)

The title compound was prepared by the methods summarized in Example 78,except for using the method of Example 15 instead of Example 14.Structure assignment was supported by elemental analysis.

[α]_(D) -33.3°; [α]₃₆₅ -122.2° (methanol)

Analysis. Calcd. for C₃₂ H₄₅ N₅ O₇.HCl.1/2H₂ O: C, 58.48; H, 7.21; N,10.66. Found: C, 58.45; H, 7.18; N, 10.56.

Example 80 Renin Inhibition Activity

The results of renin inhibition activity (human renin test) with respectto certain of the preferred embodiments of the compounds of Formula Iare set forth in Table I following.

                  TABLE I                                                         ______________________________________                                        Compound Example No.                                                                            % Inhibition                                                ______________________________________                                        58                26                                                          63                23                                                          64                22                                                          69                43                                                          70                25                                                          73                21                                                          74                28                                                          77                73                                                          ______________________________________                                         ##STR4##

What is claimed is:
 1. A method of promoting an antihypertensive effectin an animal in need thereof comprising administering thereto anantihypertensively effective amount of a compound of the formulaorpharmaceutically acceptable salts thereof wherein R₁ is: (a) hydrogen;or (b) alkyl of 1 to 6 carbon atoms, inclusive;wherein R₂ is: (a) alkylof 1 to 6 carbon atoms, inclusive; or (b) ##STR5## m being either zero,1 or 2; wherein R₃ is: (a) hydrogen; or (b) alkyl of 1 or 2 carbonatoms, inclusive;wherein R₄ is: (a) phenyl, phenyl substituted by alkylof from 1 to 6 carbon atoms, inclusive; orwherein R₅ is: (a) hydrogen;or (b) alkyl of 1 to 6 carbon atoms, inclusive;wherein R₆ is: (a)carboxy; (b) alkoxycarbonyl of 2 to 7 carbon atoms, inclusive; (c) CONH₂; (d) N,N-dialkylcarbamoyl of 3 to 7 carbon atoms, inclusive; (e)hydroxy; or (f) alkanoyloxy of 2 to 7 carbon atoms, inclusive; whereinR₇, R₈, and R₉ are H or alkyl of 1 to 6 carbon atoms, and wherein R₇, R₈and R₉ are the same or different;wherein R₁₀ is: (a) hydrogen; (b)hydroxy; or (c) alkoxycarbonyloxy wherein the alkoxy portion is from 1to 6 carbon atoms, inclusive; wherein n is an integer of from 3 to 10inclusive and the pharmacologically acceptable acid addition saltsthereof.
 2. A method according to claim 1 wherein R₆ is alkoxycarbonylof 2 to 7 carbon atoms.
 3. A method according to claim 1 wherein R₁ ishydrogen.
 4. A method according to claim 1 wherein R₂ is ##STR6## mbeing 0, 1, or
 2. 5. A method according to claim 4 wherein m is 1 or 2.6. A method according to claim 1 wherein R₃ is hydrogen.
 7. A methodaccording to claim 1 wherein R₅ is hydrogen.
 8. A method according toclaim 1 wherein R₇, R₈, and R₉ are H or alkyl of 1 to 6 carbon atoms,and may be the same or different and R₁₀ is hydroxy.
 9. A methodaccording to claim 8 wherein two of R₇, R₈, and R₉ are alkyl of 1 to 6carbon atoms and the other is hydrogen.
 10. A method according to claim1 wherein R₄ is phenyl.
 11. A method according to claim 1 wherein saidcompound is selected fromO-(2-methylpropoxycarbonyl)-2,3,6-trimethyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride,O-(2-methylpropoxycarbonyl)-2-methyltyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride,O-(2-methylpropoxycarbonyl)-2-methyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]-glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride,O-(2-methylpropoxycarbonyl)-3-t-butyl-1-tyrosyl-D-methionylglycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride,O-(2-methylpropoxycarbonyl)-3-t-butyltyrosyl-[4-(methylsulfinyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride,3-t-butyl-L-tyrosyl-[4-(methylsulfonyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxo-hexyl)-L-phenylalaninamidemonohydrochloride,3-t-butyl-D-tyrosyl-[4-(methylsulfonyl)-D-2-aminobutanoyl]glycyl-N-(6-methoxy-6-oxo-hexyl)-L-phenylalaninamidemonohydrochloride,2,4-dimethyl-3-hydroxyphenylalanyl-D-methionyl-glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride.
 12. A method according to claim 11 wherein saidcompound is2,4-dimethyl-3-hydroxyphenylalanyl-D-methionyl-glycyl-N-(6-methoxy-6-oxohexyl)-L-phenylalaninamidemonohydrochloride.
 13. A method according to claim 12, wherein saidcompound is administered in combination with a non-toxicpharmaceutically acceptable carrier.
 14. A method according to claim 13,wherein said compound is administered orally.